Antibody Therapeutics最新文献

{"title":"Integrating fab phage and yeast display through seamless transfer of paired heavy- and light-chain libraries for efficient antibody discovery.","authors":"Wei Zhang, Hao Ye, Xingrun Zhang, Cheng Liao","doi":"10.1093/abt/tbag024","DOIUrl":"10.1093/abt/tbag024","url":null,"abstract":"<p><strong>Background: </strong><i>In vitro</i> display technologies, especially phage and yeast display, are revolutionary tools in antibody discovery, enabling high-throughput screening and engineering. Previous efforts to integrate phage and yeast display for synergistic antibody discovery have predominantly focused on scFvs and sdAbs.</p><p><strong>Methods: </strong>Here, we developed an integrated phage-yeast display platform for efficient Fab antibody discovery. We transferred paired Fab libraries from phage output into yeast display vectors while preserving VH-VL pairings with the engineered compatible Fab display vectors that we developed for both phage and yeast. Specifically, we identified restriction enzyme sites that are rare in antibody variable regions and designed novel signal peptides compatible with these sites for Fab display. These signal peptides performed at least as well as commonly used benchmarks (such as PelB or StII for phage display, and AGA2 or MFAL1 for yeast display) in bio-panning experiments. Our modular vector architecture supports straightforward library shuttling across mouse-derived, fully human, and naïve Fab libraries.</p><p><strong>Results: </strong>Using a mouse immune Fab library, we applied our integrated platform to isolate antibodies against a soluble protein. Following two rounds of liquid-phase phage display and four rounds of fluorescence-activated cell sorting combined with a yeast-based receptor-blocking screening method developed herein, we successfully isolated antigen-specific Fabs with sub-nanomolar affinities and potent receptor-blocking activity.</p><p><strong>Conclusions: </strong>Our integrated approach leverages the capacity of phage display to screen large Fab libraries while harnessing the strength of yeast display for functional screening, exemplified here by the successful identification of receptor-blocking antibodies, thereby streamlining the discovery of high-quality Fab candidates.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"9 3","pages":"300-311"},"PeriodicalIF":4.8,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13317740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148362743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytotoxic activity and safety characterization of IMV-M™, a MUC16 × DR5 bispecific antibody.","authors":"Victor S Goldmacher, Iosif M Gershteyn","doi":"10.1093/abt/tbag021","DOIUrl":"10.1093/abt/tbag021","url":null,"abstract":"<p><strong>Background: </strong>IMV-M is a MUC16 × DR5 bispecific antibody that has demonstrated MUC16-selective antitumor activity. However, it remained unclear whether multisite binding to MUC16 is required for cytotoxicity, and whether circulating CA125 (soluble MUC16) or antidrug antibodies could affect efficacy or cause toxicity.</p><p><strong>Methods: </strong>A comparative analysis of three bispecific antibodies, IMV-M (sofituzumab × DR5), 11D10 × DR5, and fluor × DR5, sharing an identical IgG1-anti-DR5 scFv architecture, was performed. Sofituzumab binds to multiple epitopes on a single MUC16 molecule, whereas 11D10 binds a single MUC16 epitope, and fluor does not bind any human antigen. Antibody binding to shed and cell-surface MUC16 was evaluated by ELISA and flow cytometry. Cytotoxicity was assessed in a MUC16⁺/DR5⁺ tumor cell line and MUC16^-/DR5⁺ hepatic cell lines. Additional studies examined the effects of soluble CA125 and Fc-directed polyclonal antibodies on IMV-M activity.</p><p><strong>Results: </strong>IMV-M bound MUC16 to a markedly higher extent than the 11D10 × DR5 comparator, consistent with its multivalent engagement, while binding of fluor × DR5 to MUC16 was negligible. Only IMV-M induced potent cytotoxicity in MUC16⁺ tumor cells, whereas 11D10 × DR5 and fluor × DR5 control antibodies were inactive, even at concentrations where binding of 11D10 × DR5 exceeded that of cytotoxic concentrations of IMV-M. These findings support the notion that multivalent clustering on MUC16 is required for apoptosis. IMV-M showed no significant cytotoxicity toward hepatic cell lines, even in the presence of Fc-directed polyclonal antibodies or clinically relevant concentrations of soluble CA125.</p><p><strong>Conclusions: </strong>These findings suggest that IMV-M cytotoxic activity requires clustering on MUC16, that CA125 at clinically relevant concentrations does not mediate IMV-M neutralization, and that aggregate formation with secondary antibodies or soluble MUC16 does not induce off-target toxicity.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"9 3","pages":"293-299"},"PeriodicalIF":4.8,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13317741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148362776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The evolving landscape of enzymatic technologies for precision synthesis of antibody-drug conjugates.","authors":"Thuc Oanh Hoang, Arshad J Ansari, Yong Zhang","doi":"10.1093/abt/tbag020","DOIUrl":"10.1093/abt/tbag020","url":null,"abstract":"<p><p>Precise control over how and where small-molecule drugs are covalently attached to monoclonal antibodies is increasingly vital for creating consistently efficacious and safe antibody-drug conjugates (ADCs) as powerful targeted therapies. Enzymatic conjugation methods have gained considerable attention for their abilities to efficiently install payloads at defined locations under mild and predictable conditions. This work provides a comprehensive review of current enzymatic technologies for site-specific ADC construction, organized by the biological origin of enzymes. Among various enzyme-based conjugating approaches, a special focus is given to the emerging ADP-ribosyl cyclase-enabled ADC (ARC-ADC) platform. By utilizing genetically fused CD38, a member of the ARC family, together with its dinucleotide-derived inhibitor, site-specific ADCs with defined drug-to-antibody ratios in varied formats could be facilely produced with demonstrated efficacy and specificity in preclinical models of different types of cancer. Unlike most enzymatic methods requiring recognition tags or external catalytic steps, ARC-ADC provides a fully integrated, modular strategy for streamlined ADC discovery and development.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"9 3","pages":"259-272"},"PeriodicalIF":4.8,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13317745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148362758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antibody-oligonucleotide conjugates: an emerging modality for precision RNA therapeutics.","authors":"Chen-Hsu Yu, Summer Y Y Ha, Zhiqiang An, Kyoji Tsuchikama, Wenbo Li","doi":"10.1093/abt/tbag022","DOIUrl":"10.1093/abt/tbag022","url":null,"abstract":"<p><p>RNA-targeting therapeutics have enormous potential to precisely target disease-causing RNAs, extending beyond the traditional limits of \"druggability\" for small molecules, antibodies, and protein-targeting cell therapies. However, one crucial limitation is that RNA-targeting drug modalities (such as oligonucleotides) cannot effectively reach diseased tissue or cell types. Antibody-oligonucleotide conjugates (AOCs) emerge as a promising frontier in aiding RNA therapeutics by harnessing antibodies to deliver drug modalities to target specific RNAs in desired tissues or cells. In this Review, we summarize the critical components of AOCs, key considerations for their design and manufacturing, ongoing AOCs in preclinical/clinical development, and disease indications. We discuss the current hurdles to improving AOC efficacy and extending its application, concluding with an outlook on the unique opportunities offered by AOCs beyond traditional oligonucleotides and small-molecule antibody-drug conjugates. We propose that, with focused efforts to overcome key challenges, AOCs have the potential to transform RNA therapeutics, offering treatment options for many previously untreatable diseases.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"9 3","pages":"273-292"},"PeriodicalIF":4.8,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13317746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148362808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Generative AI-driven <i>de novo</i> design of high-affinity, epitope-specific antibodies targeting the CD93-IGFBP7 axis for cancer immunotherapy.","authors":"Yixin Qian, Youxin Feng, Ming Zou, Huiyu Cai, Jintong Ye, Teng Song, Ping Li, Jian Tang, Mi Deng","doi":"10.1093/abt/tbag019","DOIUrl":"10.1093/abt/tbag019","url":null,"abstract":"<p><strong>Background: </strong>CD93 is an emerging immune checkpoint. Blocking its interaction with insulin-like growth factor-binding protein-7 (IGFBP7) restores antitumor immunity, yet discovering high-affinity antibodies against this specific functional epitope remains a formidable challenge for traditional methods.</p><p><strong>Methods: </strong>We employed a proprietary generative artificial intelligence (AI) model, GeoFlow, to <i>de novo</i> design antibodies targeting the predicted binding epitope of a reference antibody 7F3. A library constructed from 10⁵ sequences was screened via phage display, and the lead candidate, 7-4_com10, was validated through biolayer interferometry, flow cytometry, and <i>in vivo</i> efficacy studies.</p><p><strong>Results: </strong>To dissect the contribution of endothelial CD93 to immunotherapy resistance, we utilized an endothelial-specific conditional knockout model in MB49 bladder cancer, where the loss of endothelial CD93 significantly sensitized tumors to PD-1 inhibition. The genetic findings identified endothelial CD93 as a fundamental driver of immunotherapy resistance and provided the rationale for our GeoFlow generative AI platform, which was employed to <i>de novo</i> design ~10⁵ candidates targeting the IGFBP7-binding interface on CD93. Our lead candidate, 7-4_com10, demonstrated superior affinity and more potent functional blockade of the CD93-IGFBP7 axis compared to the reference 7F3. Crucially, 7-4_com10 sensitized H22 solid tumors to anti-PD-1 therapy <i>in vivo</i>, which confirmed that 7-4_com10 successfully targeted the identified immunosuppressive axis and pharmacologically phenocopied the benefits of genetic endothelial ablation.</p><p><strong>Conclusions: </strong>This study validated generative AI for designing epitope-specific antibodies with superior potency, offering a robust candidate for next-generation immunotherapy.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"9 3","pages":"323-331"},"PeriodicalIF":4.8,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13463625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148725925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TROP2 antibody-drug conjugate: unique epitope engagement drives differentiated efficacy.","authors":"Hang Chen, Xiaoshan Min, Qingwen Cheng, Lin Liu, Brittany Jiang, Yinan Wu, Juliet G Carbon, Daeun Nam, Jing Zhou, Silvia C Bobeica, Shih-Ping Chen, Jennifer Li, Nikolai Sharkov, Subhadra Dash, Shidong Ma, Sujun Hua, Fang Wang, Andres Rojas, Guorui Zhao, Shenjun Li, Hui Wang, Qinbin Zhang, Jing Tao, Zhan Jiao Yu, Lili Wang, Wei Zhang, Yuanhao Li, Jing Jiang, Jianmin Fang, Zhulun Wang","doi":"10.1093/abt/tbag018","DOIUrl":"10.1093/abt/tbag018","url":null,"abstract":"<p><strong>Background: </strong>Trophoblast cell surface antigen 2 (TROP2) is frequently overexpressed in various cancers and is associated with poor prognosis. While TROP2-targeted antibody-drug conjugates (ADCs), such as sacituzumab govitecan, sacituzumab tirumotecan, and datopotamab deruxtecan (DXD), achieved clinical success, the mechanisms underlying resistance to these therapies remain incompletely understood. Consequently, the full therapeutic potential of TROP2 ADCs has yet to be comprehended.</p><p><strong>Methods: </strong>We developed R7059-DXD, a novel TROP2-targeted ADC featuring an antibody that binds an epitope that is distinct from those recognized by sacituzumab and datopotamab. The structural basis of epitope recognition was elucidated using cryo-electron microscopy (cryo-EM), complemented by binding affinity analyses across multiple surface-expressed TROP2 variants. Functional activity was systematically evaluated through <i>in vitro</i> antibody-dependent cellular cytotoxicity (ADCC) assays, <i>in vitro</i> ADC-mediated killing assays, and <i>in vivo</i> efficacy studies in tumor models, including resistant lines.</p><p><strong>Results: </strong>The R7059 antibody exhibited high binding affinity across multiple TROP2 variants, addressing a key resistance mechanism. The cryo-EM structure analysis revealed that the R7059 epitope lies in the N-terminal domain of TROP2 and is distinct from the sacituzumab and datopotamab epitopes. Functionally, R7059 demonstrated potent antitumor activity through both ADCC-dependent and independent mechanisms, suggesting additional signaling effects. The R7059 ADC demonstrated robust efficacy in multiple preclinical tumor models, including those resistant to approved TROP2 ADCs.</p><p><strong>Conclusions: </strong>R7059-DXD is a differentiated, epitope-distinct TROP2-targeted ADC with the potential to overcome resistance to existing therapies. These findings support its further clinical development as a novel treatment for TROP2-expressing malignancies, including in patients previously treated with sacituzumab- or datopotamab-based regimens.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"9 3","pages":"248-258"},"PeriodicalIF":4.8,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13317744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148362737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of SDP0505: a first-in-class HER3 × c-Met bispecific ADC, demonstrates potent antitumor activity in EGFR TKI-resistant NSCLC, CRC, and beyond.","authors":"Li-Min Wang, Changyong Yang, Simeng Chen, Xing Sun, Yunan Tian, Jieqiong Zhang, Xiaomeng Gao, Dan Li, Wei Zhang, Yali Hu, Jimin Yuan, Qumiao Xu, Xiyang Liu, Long Zhang, Qianqian Yu, Cheng Liao","doi":"10.1093/abt/tbag015","DOIUrl":"10.1093/abt/tbag015","url":null,"abstract":"<p><strong>Background: </strong>Despite the success of third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC), acquired resistance remains an unmet need. Although human epidermal growth factor receptor 3 (HER3) and c-Met upregulation are key mechanisms of this resistance, the rationale for simultaneously targeting both to overcome this challenge remains unexplored.</p><p><strong>Methods: </strong>HER3 and c-Met expression were evaluated by immunohistochemistry in 270 clinical samples, including EGFR TKI-resistant NSCLC, lung adenocarcinoma (LUAD), gastric cancer, and colorectal cancer (CRC). The binding affinity of SDP0505 was measured by surface plasmon resonance and enzyme-linked immunosorbent assay, internalization was monitored using Incucyte, and <i>in vitro</i> cytotoxicity was assessed via CellTiter-Glo assay. The <i>in vivo</i> anti-tumor activities were investigated in cell-derived and patient-derived xenograft (PDX) models. Pharmacokinetics and repeated-dose toxicity were studied in cynomolgus monkeys.</p><p><strong>Results: </strong>Immunohistochemical analyses revealed spatial colocalization of HER3 and c-Met in EGFR TKI-resistant NSCLC specimens. Furthermore, high co-expression was observed in 58% of EGFR-mutant LUAD and 95% of CRC cases. Consequently, SDP0505 was developed with optimal antigen-binding affinity and antibody format through comprehensive screening. In HER3/c-Met dual-positive cell lines, SDP0505 demonstrated enhanced cell binding and internalization over the in-house synthesized U3-1402 analog. Superior <i>in vivo</i> antitumor efficacy was also observed in multiple NSCLC and CRC models, including EGFR TKI-resistant PDX models. Moreover, SDP0505 exhibited favorable pharmacokinetic and safety profiles in cynomolgus monkeys.</p><p><strong>Conclusions: </strong>SDP0505 represents a novel HER3 × c-Met ADC with superior internalization and anti-tumor activity in preclinical models, especially in EGFR TKI-resistant PDX models. These results supported the initiation of a Phase I clinical trial in China.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"9 2","pages":"201-213"},"PeriodicalIF":4.8,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13175982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147964823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A hyperimmune ovine antibody-based therapeutic candidate against Crimean-Congo haemorrhagic fever virus targeted to the Gn and Gc glycoproteins: high antibody levels with neutralization activity but lack of protective efficacy in a mouse model.","authors":"Emma Kennedy, Stephen Findlay-Wilson, Sarah Webster, Annahita Rajabzadeh, Susan Fotheringham, Linda Easterbrook, Adam Chambers, Mine Aksular, Robert Possee, Sandra Smith, Neville Pope, Aled Griffiths, Ulrike Arnold, David Jackson, Inés Ruedas-Torres, Francisco Javier Salguero, Stuart Dowall","doi":"10.1093/abt/tbag017","DOIUrl":"https://doi.org/10.1093/abt/tbag017","url":null,"abstract":"<p><strong>Background: </strong>Crimean-Congo haemorrhagic fever virus (CCHFV) is a tick-borne pathogen that has a wide geographical range and has the potential to cause severe disease in those infected. There are no currently approved vaccines or therapeutics, so the development and assessment of new approaches are urgently required.</p><p><strong>Methods: </strong>A polyclonal antibody-based therapeutic was developed based on immunization of sheep with the major glycoprotein antigens from CCHFV. Along with purified immunoglobulin G (IgG) from hyperimmune sera, fragmentation of the F(ab')2 region was also performed. The pharmacokinetic properties were assessed in mice, and efficacy was ascertained in a live CCHFV challenge model.</p><p><strong>Results: </strong>Candidate polyclonal antibody-based therapies were developed, demonstrating strong binding to the CCHFV envelope glycoprotein and neutralizing activity. The ovine whole IgG demonstrated stability post-delivery compared to a rapid reduction of the F(ab')2 fragment in the circulation. Efficacy testing when delivered either as a single dose before challenge or as daily dosing for 7 days starting on the day of challenge showed no demonstrable evidence of protection against infection.</p><p><strong>Conclusions: </strong>Despite protection observed from vaccine candidates using the CCHFV glycoprotein as an antigen and administration of convalescent sera, the ovine antibody-based therapeutics did not confer similar efficacious effects in the mouse preclinical model.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"9 2","pages":"179-190"},"PeriodicalIF":4.5,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13175991/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147964816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ivonescimab and other anti-programmed death-1/ligand 1 (PD-(L)1)/vascular endothelial growth factor (VEGF) bispecific antibodies: progress and prospects in cancer therapy.","authors":"Cunnan Dong, Xue Wang","doi":"10.1093/abt/tbag016","DOIUrl":"10.1093/abt/tbag016","url":null,"abstract":"<p><p>In cancer therapy, the synergistic interaction between immunotherapy and anti-angiogenic therapy has been validated by both preclinical and clinical studies, and has laid the foundation for the development of anti-PD-(L)1/VEGF bispecific antibodies. In the HARMONi-2 trial, ivonescimab demonstrated superior efficacy over pembrolizumab for the first time. This milestone may open a new era of immunotherapy with bispecific antibodies replacing anti-PD-1 monoclonal antibodies. Subsequently, the HARMONi-6 trial confirmed that ivonescimab combined with chemotherapy also outperformed tislelizumab plus chemotherapy, adding further evidence. Currently, dozens of anti-PD-(L)1/VEGF bispecific antibodies with distinct molecular structures have entered clinical stages; and only ivonescimab has completed Phase 3 clinical trial validation in multiple clinical trials and obtained approval in China. A growing body of clinical evidence indicates that in immunotherapy-sensitive tumors (e.g. lung cancer), bispecific antibodies have demonstrated superior efficacy compared with monoclonal antibodies. Even in tumors traditionally refractory to immunotherapy (such as colorectal cancer and pancreatic cancer), bispecific antibodies exhibit promising therapeutic effects while maintaining a favorable safety profile. Nevertheless, several issues require further investigation, such as predictive biomarkers and resistance mechanisms. Future investigations surrounding this class of agents are highly anticipated, including anti-PD-(L)1/VEGF bispecific antibodies-based combination therapy in a broader range of tumor types, as well as the development of trispecific antibodies and bispecific antibody-drug conjugates.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"9 2","pages":"191-200"},"PeriodicalIF":4.8,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13175990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147964842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical characterization of IBD0333, a novel CD24×4-1BB bispecific antibody with tumor-dependent agonistic activity for cancer immunotherapy.","authors":"Dong-Cheng Jiang, Dan-Dan Zhou, Xiao-Rui Xu, Xiao-Ling Jiang, Liu-Song Yin, Cai-Yun Zhong, Qing-Fang Miao","doi":"10.1093/abt/tbag014","DOIUrl":"10.1093/abt/tbag014","url":null,"abstract":"<p><strong>Background: </strong>The immunosuppressive nature of tumor microenvironment (TME) limits the efficacy of current immunotherapies. Bispecific antibodies (bsAbs) offer a promising strategy to overcome this challenge by enabling localized immune activation. Specifically, simultaneously targeting the \"don't eat me\" signal CD24 on tumor cells and the co-stimulatory receptor 4-1BB on immune cells may provide potent anti-tumor effects while mitigating the systemic toxicity typically associated with conventional 4-1BB agonists. Here, we present the preclinical evaluation of IBD0333, a novel bsAb targeting CD24 and 4-1BB.</p><p><strong>Methods: </strong>The binding affinity of IBD0333 to CD24 and 4-1BB was evaluated, and its pharmacodynamic effects were assessed through multiple <i>in vitro</i> assays. Anti-tumor efficacy of IBD0333 was evaluated using C57BL/6J-h4-1BB humanized mouse models <i>in vivo</i>, while pharmacokinetic and safety profiles were further investigated in cynomolgus monkeys.</p><p><strong>Results: </strong>IBD0333 exhibited high-binding affinity to both human and cynomolgus monkey CD24 and 4-1BB proteins. Its agonistic activity toward 4-1BB was strictly dependent on CD24, as evidenced by potent NF-κB activation and cytokine induction only in the presence of CD24-positive tumor cells. IBD0333 also demonstrated appropriate FcγR binding and no-detectable antibody-dependent cellular cytotoxicity/complement-dependent cytotoxicity activity. In a syngeneic tumor model, complete tumor regression was achieved at doses of 1 and 3 mg/kg. Furthermore, IBD0333 was well tolerated in cynomolgus monkeys with no observed immunotoxicity or hepatotoxicity, and the no-observed-adverse-effect level following repeated administration was established as 120 mg/kg.</p><p><strong>Conclusion: </strong>IBD0333 is a tumor-conditionally activated anti-CD24×4-1BB bsAb that demonstrates potent antitumor efficacy along with a favorable safety and pharmacokinetic profile. These findings support its further clinical development.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"9 2","pages":"168-178"},"PeriodicalIF":4.8,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13175977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147964806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}