Antibody Therapeutics最新文献

{"title":"Affinity-optimized TROP2 antibodies support potent antitumor activity in antibody-drug conjugates.","authors":"Aiko Yamaguchi, Junping Hong, Leike Li, Kiyotaka Kobayashi, Chisato M Yamazaki, Summer Y Y Ha, Yasuaki Anami, Wei Xiong, Junquan Liu, Zhiqiang An, Ningyan Zhang, Kyoji Tsuchikama","doi":"10.1093/abt/tbag011","DOIUrl":"https://doi.org/10.1093/abt/tbag011","url":null,"abstract":"<p><strong>Background: </strong>Trophoblast cell surface antigen 2 (TROP2) is frequently overexpressed in epithelial tumors and is associated with poor prognosis, making it an attractive therapeutic target. Antibody-drug conjugates (ADCs) directed against TROP2 show clinical benefit, but expression in normal tissues such as skin raises concerns about on-target, off-tumor toxicity. Strategies that improve antitumor efficacy without increasing toxicity are needed.</p><p><strong>Methods: </strong>Using an in-house phage library, we identified and characterized a novel fully human monoclonal antibody recognizing a unique conformational epitope of TROP2 with reduced binding affinity. This antibody was engineered into homogeneous ADCs carrying auristatin and/or duocarmycin payloads. Comparative studies with a surrogate of sacituzumab govitecan were performed in TROP2-expressing tumor models.</p><p><strong>Results: </strong>The novel ADCs demonstrated remarkable antitumor activity in mouse xenograft and syngeneic tumor models. Despite lower binding affinity, the novel antibody exhibited potent efficacy, suggesting that epitope selection and affinity tuning can be leveraged to enhance therapeutic outcomes.</p><p><strong>Conclusions: </strong>Novel anti-TROP2 ADCs offer a promising approach for assuring efficacy while potentially mitigating toxicity. Optimization of antibody binding properties may enable the development of safer and more effective TROP2-targeted therapeutics.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"9 2","pages":"127-138"},"PeriodicalIF":4.5,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13070557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147677355","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":"Challenges and solutions for upstream processing of complex biologics.","authors":"Shuya Xu, Yunlong Wang, Yawen Yu, Felix Zhu, Ying Li","doi":"10.1093/abt/tbag008","DOIUrl":"https://doi.org/10.1093/abt/tbag008","url":null,"abstract":"<p><p>Unlike conventional monoclonal antibodies, complex biologics-such as bispecific antibodies and fusion proteins-often face challenges including lower expression levels, higher mispairing rates, and greater sensitivity to culture conditions, which can collectively limit both titer and product quality. Leveraging process development case studies, this review systematically explores upstream bioprocessing strategies aimed at mitigating these challenges, with a focus on titer enhancement, lactate metabolism regulation, acidic charge variants control, reduction of aggregates and fragments, and glycosylation optimization. Finally, a perspective toward future upstream development strategies is discussed.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"9 2","pages":"139-149"},"PeriodicalIF":4.5,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13070570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147677325","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":"Durable disease control following treatment with ALMB-0168, a novel Cx43 hemichannel agonist monoclonal antibody, in femoral osteosarcoma with lung metastases after chemotherapy failure: a case report.","authors":"Xianbiao Xie, Yiying Bian, Xiugao Yang, Yanfeng Zhang, Junqiang Yin, Jingnan Shen","doi":"10.1093/abt/tbag007","DOIUrl":"https://doi.org/10.1093/abt/tbag007","url":null,"abstract":"<p><p>Limited progress has been made over the past three decades in improving survival for patients with osteosarcoma after standard therapy. ALMB0168 is a first-in-class therapeutic antibody agonist targeting Cx43 hemichannels and has demonstrated to suppress the growth and migration of osteosarcoma in preclinical studies. This article presents a case of a patient with bilateral femoral osteosarcoma who was treated with ALMB0168. The patient, who had metastases in both contralateral limb and lung with ≥3 prior lines chemotherapy, showed immediate lesion shrinkage upon treatment and subsequently achieved durable partial response with a long duration of the response. The patient had a progression-free survival of 23 months to date, and the treatment was still ongoing. This case highlights that ALMB0168 may represent a promising treatment option for patients with metastatic or unresectable osteosarcoma after standard chemotherapy.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"9 2","pages":"119-124"},"PeriodicalIF":4.5,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13042229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147610171","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":"Analysis of the use of monoclonal antibodies in the treatment of Crohn's disease.","authors":"Alexander V Blagov, Marina D Sazonova, Anastasia I Ryzhkova, Vasily P Karagodin, Mikhail A Popov, Egor Yu Budnikov, Alessio L Ravani, Alexander N Orekhov, Margarita A Sazonova, Yuri V Arkhipenko","doi":"10.1093/abt/tbag006","DOIUrl":"https://doi.org/10.1093/abt/tbag006","url":null,"abstract":"<p><p>Crohn's disease (CD) is a chronic inflammatory bowel disease with increasing global prevalence, significantly impacting patients' quality of life and healthcare costs. The introduction of monoclonal antibodies has revolutionized CD management, offering targeted therapy against specific inflammatory pathways. This review systematically analyzes the current state of monoclonal antibody therapy, including anti-TNF-α agents (infliximab, adalimumab, certolizumab pegol), anti-integrin antibodies (vedolizumab), and anti-cytokine therapies (ustekinumab, risankizumab). Despite remarkable therapeutic advances, significant limitations persist, including primary non-response (20%-40%), secondary loss of response (13%-20% annually), immunogenicity, safety concerns, and substantial economic burden. We propose evidence-based strategies to address these challenges, including therapeutic drug monitoring, combination therapy, and personalized medicine approaches. Furthermore, we identify promising novel therapeutic targets such as IL-36, IL-17C, SMAD7, TL1A, complement components, and microbiome-related factors. Targeting two or more specific targets simultaneously appears to be a promising direction of research for the development of bi- and polyspecific monoclonal antibodies capable of interfering with multiple pathological pathways in CD. The integration of advanced antibody engineering, personalized medicine, and innovative delivery systems represents the future direction for overcoming current limitations. Achieving sustained remission for all patients through safe, effective, and accessible therapeutic interventions remains the ultimate goal in CD management.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"9 2","pages":"101-118"},"PeriodicalIF":4.5,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13042251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147610189","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":"Correction to: CAR NK cell therapy for solid tumors: potential and challenges.","authors":"","doi":"10.1093/abt/tbag004","DOIUrl":"https://doi.org/10.1093/abt/tbag004","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1093/abt/tbaf019.].</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"9 1","pages":"100"},"PeriodicalIF":4.5,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12967325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147390481","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 glycoengineered anti-ROR1 antibody, GE-zilovertamab, selectively enhances antibody-dependent cellular cytotoxicity against chronic lymphocytic leukemia.","authors":"Md Kamrul Hasan, George Widhopf Ii, Thomas J Kipps","doi":"10.1093/abt/tbag001","DOIUrl":"https://doi.org/10.1093/abt/tbag001","url":null,"abstract":"<p><p>Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is selectively expressed on chronic lymphocytic leukemia (CLL) B cells and certain cancers, but is absent from normal B cells and healthy adult tissues. GE-zilovertamab, an afucosylated anti-ROR1 IgG1 antibody, is engineered to increase FcγRIIIA binding and thereby enhance antibody-dependent cellular cytotoxicity (ADCC). Co-culture assays were performed using CLL cell lines (MEC1, MEC1-ROR1) and primary CLL cells with Jurkat-Lucia™ NFAT-CD16, NK, or peripheral blood mononuclear cell effectors. Treatments included the anti-CD20 mAb rituximab, anti-ROR1 mAbs (GE-zilovertamab, zilovertamab), and the endocytosis inhibitor prochlorperazine, and ADCC was quantified. GE-zilovertamab showed significantly higher ADCC than its parental antibody and activity that was comparable to that of rituximab. We find that the endocytosis inhibitor prochlorperazine further increased this effect. GE-zilovertamab is a promising next-generation immunotherapeutic for CLL, combining selective targeting of ROR1 with the potential to reduce therapy-induced immunodeficiency compared with anti-CD20 antibodies.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"9 1","pages":"70-75"},"PeriodicalIF":4.5,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12967326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147391443","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 novel bispecific antibody targeting OX40L and TNFα for the targeted treatment of rheumatoid arthritis.","authors":"Qun Zhang, Shuliang Song","doi":"10.1093/abt/tbag003","DOIUrl":"https://doi.org/10.1093/abt/tbag003","url":null,"abstract":"<p><strong>Background: </strong>Rheumatoid arthritis is driven by T cell dysregulation and TNFα-mediated inflammation. Dual targeting of OX40 ligand (OX40L) and tumor necrosis factor alpha (TNFα) may offer synergistic therapeutic effects.</p><p><strong>Methods: </strong>A murine monoclonal antibody against OX40L (KD-0025) was generated and humanized via complementarity-determining region grafting. A bispecific construct incorporating single-chain variable fragments for OX40L and TNFα was expressed in CHO-K1 cells. High-expressing clones were selected, and antibodies were purified using Protein A/G chromatography. Binding to 293 T-OX40L cells, A172 cells, and TNFα was assessed by flow cytometry and ELISA. Functional blockade of OX40L-OX40 and TNFα-TNFR pathways was evaluated using a luciferase reporter assay. Binding kinetics were measured using the ForteBio Octet system. <i>In vivo</i> efficacy was tested in a collagen antibody-induced arthritis (CAIA) mouse model.</p><p><strong>Results: </strong>The parental KD-0025 antibody showed EC50 values of 0.4024 μg/ml (human OX40L) and 0.1126 μg/ml (monkey OX40L), with an IC50 of 0.07893 μg/ml. Humanized KA-3966 improved EC50 (0.1374 μg/ml) and had an IC50 of 0.5997 μg/ml. The bispecific antibody KA-5484 demonstrated superior affinity (KD = 1.90 × 10^-10 M) and dual-target binding (EC50: 0.1062 and 0.06240 μg/ml for human and monkey OX40L, respectively). It blocked OX40L-OX40 (IC50 = 0.1318 μg/ml) and showed 15-20% greater TNFα pathway suppression than the control antibody KB-1580. KA-5484 significantly reduced inflammation in the CAIA mouse model.</p><p><strong>Conclusion: </strong>A humanized bispecific antibody targeting OX40L and TNFα was successfully developed, exhibiting potent dual-target engagement and blockade. The antibody demonstrated synergistic modulation of immune and inflammatory pathways, providing a promising foundation for future preclinical development.</p><p><strong>Highlights: </strong>The novel bispecific KA-5484 binds both OX40L and TNFα with high affinity.Dual targeting of OX40L and TNFα enables synergistic immune modulation.KA-5484 outperforms control antibodies in binding and inflammatory assays.KA-5484 shows superior efficacy in mitigating arthritis in the collagen antibody-induced arthritis mouse model.Enhanced cross-species reactivity supports the translational relevance of KA-5484.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"9 1","pages":"76-85"},"PeriodicalIF":4.5,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12967327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147390190","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":"IMM2510, a novel anti-PD-L1/VEGF bispecific antibody for cancer immunotherapy.","authors":"Dianze Chen, Zhuli Wu, Xiwen Zhao, Rupal S Bhatt, Yanan Yang, Wenqi Zhu, Huang Tang, Kaili Wang, Chunli Guo, Dandan Liu, Chunmei Yang, Huiqin Guo, Xing Bai, Ruliang Zhang, Song Li, Wenzhi Tian","doi":"10.1093/abt/tbag002","DOIUrl":"https://doi.org/10.1093/abt/tbag002","url":null,"abstract":"<p><strong>Background: </strong>Dual inhibition of PD-1/PD-L1 and VEGF/VEGFR pathways is a promising strategy to overcome tumor immune evasion and inhibit angiogenesis. IMM2510 is a novel PD-L1 × VEGF bispecific antibody, constructed by fusing VEGFR1 domain 2 (VEGFR1D2) to each anti-PD-L1 heavy chain. In addition, IMM2510 incorporates an Fc region engineered for enhanced antibody-dependent cellular cytotoxicity (ADCC), enabling elimination of PD-L1-expressing tumor and stromal cells.</p><p><strong>Methods: </strong>Binding and blocking activities were assessed using enzyme-linked immunosorbent assay, surface plasmon resonance, and flow cytometry. Functional assays included Jurkat-PD-1 and VEGFR2 reporter systems, HUVEC proliferation, mixed lymphocyte reaction, and NK cell-mediated cytotoxicity. Cooperative binding with VEGF165 was evaluated biochemically and in reporter assays. Antitumor efficacy was tested in MC38-hPD-L1 syngeneic tumors, HCC827 non-small cell lung cancer (NSCLC) xenografts, and MDA-MB-231 triple-negative breast cancer (TNBC) xenografts.</p><p><strong>Results: </strong>IMM2510 bound PD-L1, VEGF-A, VEGF-B, and PlGF with high affinity, and blocked both PD-1/PD-L1 and VEGF/VEGFR interactions. It reversed PD-1-mediated T-cell inhibition, inhibited VEGF-driven endothelial proliferation, and induced potent ADCC and ADCP in killing PD-L1⁺ tumor cells. Preincubation with VEGF165 enhanced PD-L1 binding and checkpoint blockade activity, indicating cooperative binding. <i>In vivo</i>, IMM2510 induced dose-dependent tumor growth inhibition, achieving superior efficacy to parental monotherapies and their combination. Consistent efficacy was observed across multiple tumor types, including NSCLC and TNBC.</p><p><strong>Conclusions: </strong>IMM2510 combines checkpoint blockade, anti-angiogenesis, Fc-mediated effector function, and cooperative binding, resulting in superior preclinical antitumor activity across diverse tumor settings. These findings position IMM2510 as a differentiated next-generation therapeutic candidate for clinical development.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"9 1","pages":"86-99"},"PeriodicalIF":4.5,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12967328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147390474","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":"Bispecific and multispecific T-cell engagers: advancing the future of immunotherapy.","authors":"Xiaoqiang Kang, Yue Zhao, Hong Ling, Xiao Huang","doi":"10.1093/abt/tbaf026","DOIUrl":"10.1093/abt/tbaf026","url":null,"abstract":"<p><p>T-cell engagers (TCEs) represent an emerging class of immunotherapies that harness T cells' cytotoxic power to eliminate diseased cells-a transformative future therapeutic strategy. TCEs form immunological synapses to trigger potent immune responses, with proven efficacy in blood cancers; research expands their use to solid tumors via innovative molecular design and improved safety profiles. Beyond oncology, TCEs hold promise in autoimmune disorders by eliminating autoreactive cells, offering novel avenues for diseases like lupus. However, achieving optimal outcomes without disrupting immune homeostasis remains a challenge. Key obstacles-on-target off-tumor toxicity, cytokine release syndrome, tumor antigen loss, and T cell exhaustion-limit broader adoption. Current research addresses these via enhanced specificity, optimized design, improved druggability, and synergistic combinations. This review analyzes TCEs' mechanisms, challenges, innovations and applications, highlights our pipeline advances, and advocates sustained innovation to broaden TCE use across diseases.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"9 1","pages":"58-69"},"PeriodicalIF":4.5,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12813292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146012549","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":"Recent advances in structural investigations of cancer antigen mesothelin and its interactions with therapeutic antibodies.","authors":"Jingyu Zhan, Mitchell Ho, Lothar Esser, Carolyn A Maslanka, Ira Pastan, Di Xia","doi":"10.1093/abt/tbaf028","DOIUrl":"10.1093/abt/tbaf028","url":null,"abstract":"<p><p>The tumor-associated antigen mesothelin is highly expressed in many human cancers, while its expression in normal tissues is limited. Its interaction with the cancer antigen 125 promotes heterotypic cell adhesion and tumor metastasis. Mesothelin-targeted immunotherapies are being intensively investigated, which is aided by growing structural knowledge of the protein and its interactions with antibodies. Recent studies have produced a complete atomic model showing mesothelin as a compact, right-handed, conformationally flexible solenoid composed of nine layers of helices, with glycans attached at all three predicted N-glycosylation sites. Structural analyses reveal that most therapeutic antibodies target the rigid and immunogenic N-terminal domain, while a few bind to middle domain or C-terminal linear tail, revealing correlation between immunogenicity and structural stability. Crystallographic studies have also extended to the interactions between mesothelin and CA-125. These structural advances offer insights into the potential function of mesothelin and guidance for further development of therapeutic antibodies.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"9 1","pages":"38-57"},"PeriodicalIF":4.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12804176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145999449","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}