Antibody Therapeutics最新文献

{"title":"rAbDesFlow: A novel workflow for computational recombinant antibody design for healthcare engineering","authors":"Sowmya Ramaswamy Krishnan, Divya Sharma, Yasin Nazeer, Mayilvahanan Bose, Thangarajan Rajkumar, Guhan Jayaraman, Narayanan Madaboosi, M. M. Gromiha","doi":"10.1093/abt/tbae018","DOIUrl":"https://doi.org/10.1093/abt/tbae018","url":null,"abstract":"\u0000 \u0000 \u0000 Recombinant antibodies have emerged as a promising solution to tackle antigen specificity, enhancement of immunogenic potential and versatile functionalization to treat human diseases. The development of single chain variable fragments (scFv) has helped accelerate treatment in cancers and viral infections, due to their favorable pharmacokinetics and human compatibility. However, designing recombinant antibodies is traditionally viewed as a genetic engineering problem, with phage display and cell free systems playing a major role in sequence selection for gene synthesis. The process of antibody engineering involves complex and time-consuming laboratory techniques, which demand substantial resources and expertise. The success rate of obtaining desired antibody candidates through experimental approaches can be modest, necessitating iterative cycles of selection and optimization. With ongoing advancements in technology, in silico design of diverse antibody libraries, screening and identification of potential candidates for in vitro validation can be accelerated.\u0000 \u0000 \u0000 \u0000 To meet this need, we have developed rAbDesFlow, a unified computational workflow for recombinant antibody engineering with open-source programs and tools for ease of implementation.\u0000 \u0000 \u0000 \u0000 The workflow encompasses five computational modules to perform antigen selection, antibody library generation, antigen and antibody structure modeling, antigen-antibody interaction modeling, structure analysis, and consensus ranking of potential antibody sequences for synthesis and experimental validation. The proposed workflow has been demonstrated through design of recombinant antibodies for the ovarian cancer antigen Mucin-16 (CA-125).\u0000 \u0000 \u0000 \u0000 This approach can serve as a blueprint for designing similar engineered molecules targeting other biomarkers, allowing for a simplified adaptation to different cancer types or disease-specific antigens.\u0000","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":" 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141668754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HBsAg and TLR7/8 dual-targeting antibody-drug conjugates induce sustained anti-HBV activity in AAV/HBV mice: a preliminary study","authors":"Xinya Ye, Xiaoqing Chen, Han Liu, Yichao Jiang, Chengyu Yang, Tao Xu, Ziyou Chen, Yalin Wang, Fentian Chen, Xue Liu, Hai Yu, Quan Yuan, Ningshao Xia, Yuanzhi Chen, Wenxin Luo","doi":"10.1093/abt/tbae016","DOIUrl":"https://doi.org/10.1093/abt/tbae016","url":null,"abstract":"\u0000 \u0000 \u0000 Hepatitis B virus (HBV) infection is a significant global health concern due to elevated immunosuppressive viral antigen levels, the host immune system’s inability to manage HBV, and the liver’s immunosuppressive conditions. While immunotherapies utilizing broadly reactive HBV neutralizing antibodies (nAbs) present potential due to their antiviral capabilities and Fc-dependent vaccinal effects, they necessitate prolonged and frequent dosing to achieve optimal therapeutic outcomes. Toll-like receptor 7/8 (TLR7/8) agonists have been demonstrated promise for the cure of chronic hepatitis B (CHB), but their systemic use often leads to intense side effects. In this study, we introduced immune-stimulating antibody conjugates (ISACs) which consist of TLR7/8 agonists 1-[[4-(aminomethyl)phenyl]methyl]-2-butyl-imidazo[4,5-c]quinolin-4-amine (IMDQ) linked to an anti-HBsAg antibody 129G1, and designated as 129G1-IMDQ. Our preliminary study highlights that 129G1-IMDQ can prompt robust and sustained anti-HBsAg specific reactions with short-term administration. This underscores the conjugate’s potential as an effective strategy for HBsAg clearance and seroconversion, offering a fresh perspective for a practical therapeutic approach in the functional cure of CHB.\u0000 \u0000 \u0000 \u0000","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":" 18","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141680503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical studies of BB-1701, a HER2-targeting eribulin-containing ADC with potent bystander effect and ICD activity.","authors":"Yang Wang, Bing Xia, Lixia Cao, Jianfeng Yang, Cui Feng, Fangdun Jiang, Chen Li, Lixia Gu, Yifan Yang, Jing Tian, Xin Cheng, Keiji Furuuchi, James Fulmer, Arielle Verdi, Katherine Rybinski, Allis Soto, Earl Albone, Toshimitsu Uenaka, Likun Gong, Tingting Liu, Qiuping Qin, Ziping Wei, Yuhong Zhou","doi":"10.1093/abt/tbae019","DOIUrl":"10.1093/abt/tbae019","url":null,"abstract":"<p><strong>Background: </strong>Several HER2-targeting antibody-drug conjugates (ADC) have gained market approval for the treatment of HER2-expressing metastasis. Promising responses have been reported with the new generation of ADCs in patients who do not respond well to other HER2-targeting therapeutics. However, these ADCs still face challenges of resistance and/or severe adverse effects associated with their particular payload toxins. Eribulin, a therapeutic agent for the treatment of metastatic breast cancer and liposarcoma, is a new choice of ADC payload with a distinct mechanism of action and safety profile.</p><p><strong>Methods: </strong>We've generated a novel HER2-tageting eribulin-containing ADC, BB-1701. The potency of BB-1701 was tested <i>in vitro</i> and <i>in vivo</i> against cancer cells where HER2-expressing levels vary in a large range. Bystander killing effect and toxin-induced immunogenic cell death (ICD) of BB-1701 were also tested.</p><p><strong>Results: </strong>In comparison with HER2-targeting ADCs with DM1 and Dxd payload, eribulin-containing ADC demonstrated higher <i>in vitro</i> cytotoxicity in HER2-low cancer cell lines. BB-1701 also effectively suppressed tumors in models resistant to DM1 or Dxd containing ADCs. Mode of action studies showed that BB-1701 had a significant bystander effect on HER2-null cells adjacent to HER2-high cells. In addition, BB-1701 treatment induced ICD. Repeated doses of BB-1701 in nonhuman primates showed favorable pharmacokinetics and safety profiles at the intended clinical dosage, route of administration, and schedule.</p><p><strong>Conclusions: </strong>The preclinical data support the test of BB-1701 in patients with various HER2-expressing cancers, including those resistant to other HER2-targeting ADCs. A phase I clinical trial of BB-1701 (NCT04257110) in patients is currently underway.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"7 3","pages":"221-232"},"PeriodicalIF":0.0,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11259758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141735158","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":"Fc engineering by monoclonal mammalian cell display for improved affinity and selectivity towards FcγRs.","authors":"Zening Wang, Minhyo Kang, Afshin Ebrahimpour, Chuan Chen, Xin Ge","doi":"10.1093/abt/tbae017","DOIUrl":"10.1093/abt/tbae017","url":null,"abstract":"<p><p>Fc optimization can significantly enhance therapeutic efficacy of monoclonal antibodies. However, existing Fc engineering approaches are sub-optimal with noted limitations, such as inappropriate glycosylation, polyclonal libraries, and utilizing fragment but not full-length IgG display. Applying cell cycle arrested recombinase-mediated cassette exchange, this study constructed high-quality monoclonal Fc libraries in CHO cells, displayed full-length IgG on cell surface, and preformed ratiometric fluorescence activated cell sorting (FACS) with the antigen and individual FcγRs. Identified Fc variants were quantitatively evaluated by flow cytometry, ELISA, kinetic and steady-state binding affinity measurements, and cytotoxicity assays. An error-prone Fc library focusing on the hinge-C_H2 region was constructed in CHO cells with a functional diversity of 7.5 × 10⁶. Panels of novel Fc variants with enhanced affinity and selectivity for FcγRs were isolated. Particularly, clone 2a-10 (G236E/K288R/K290W/K320M) showed increased binding strength towards FcγRIIa-131R and 131H allotypes with kinetic dissociation constants (K_D-K) of 140 nM and 220 nM, respectively, while reduced binding strength towards FcγRIIb compared to WT Fc; clone 2b-1 (K222I/V302E/L328F/K334E) had K_D-K of 180 nM towards FcγRIIb; clone 3a-2 (P247L/K248E/K334I) exhibited K_D-K of 190 nM and 100 nM towards FcγRIIIa-176F and 176 V allotypes, respectively, and improved potency of 2.0 ng/ml in ADCC assays. Key mutation hotspots were identified, including P247 for FcγRIIIa, K290 for FcγRIIa, and K334 for FcγRIIb bindings. Discovery of Fc variants with enhanced affinity and selectivity towards individual FcγR and the identification of novel mutation hotspots provide valuable insights for further Fc optimization and serve as a foundation for advancing antibody therapeutics development.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"7 3","pages":"209-220"},"PeriodicalIF":0.0,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11259757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141735157","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: Reforming solid tumor treatment: the emerging potential of smaller format antibody-drug conjugate.","authors":"","doi":"10.1093/abt/tbae015","DOIUrl":"https://doi.org/10.1093/abt/tbae015","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1093/abt/tbae005.].</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"7 2","pages":"188"},"PeriodicalIF":0.0,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11200679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141459768","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":"An integrated database of experimentally validated major histocompatibility complex epitopes for antigen-specific cancer therapy.","authors":"Satoru Kawakita, Aidan Shen, Cheng-Chi Chao, Zhaohui Wang, Siliangyu Cheng, Bingbing Li, Chongming Jiang","doi":"10.1093/abt/tbae011","DOIUrl":"10.1093/abt/tbae011","url":null,"abstract":"<p><p>Cancer immunotherapy represents a paradigm shift in oncology, offering a superior anti-tumor efficacy and the potential for durable remission. The success of personalized vaccines and cell therapies hinges on the identification of immunogenic epitopes capable of eliciting an effective immune response. Current limitations in the availability of immunogenic epitopes restrict the broader application of such therapies. A critical criterion for serving as potential cancer antigens is their ability to stably bind to the major histocompatibility complex (MHC) for presentation on the surface of tumor cells. To address this, we have developed a comprehensive database of MHC epitopes, experimentally validated for their MHC binding and cell surface presentation. Our database catalogs 451 065 MHC peptide epitopes, each with experimental evidence for MHC binding, along with detailed information on human leukocyte antigen allele specificity, source peptides, and references to original studies. We also provide the grand average of hydropathy scores and predicted immunogenicity for the epitopes. The database (MHCepitopes) has been made available on the web and can be accessed at https://github.com/jcm1201/MHCepitopes.git. By consolidating empirical data from various sources coupled with calculated immunogenicity and hydropathy values, our database offers a robust resource for selecting actionable tumor antigens and advancing the design of antigen-specific cancer immunotherapies. It streamlines the process of identifying promising immunotherapeutic targets, potentially expediting the development of effective antigen-based cancer immunotherapies.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"7 2","pages":"177-186"},"PeriodicalIF":0.0,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11200702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141459767","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":"Protein language models enable prediction of polyreactivity of monospecific, bispecific, and heavy-chain-only antibodies.","authors":"Xin Yu, Kostika Vangjeli, Anusha Prakash, Meha Chhaya, Samantha J Stanley, Noah Cohen, Lili Huang","doi":"10.1093/abt/tbae012","DOIUrl":"10.1093/abt/tbae012","url":null,"abstract":"<p><strong>Background: </strong>Early assessment of antibody off-target binding is essential for mitigating developability risks such as fast clearance, reduced efficacy, toxicity, and immunogenicity. The baculovirus particle (BVP) binding assay has been widely utilized to evaluate polyreactivity of antibodies. As a complementary approach, computational prediction of polyreactivity is desirable for counter-screening antibodies from <i>in silico</i> discovery campaigns. However, there is a lack of such models.</p><p><strong>Methods: </strong>Herein, we present the development of an ensemble of three deep learning models based on two pan-protein foundational protein language models (ESM2 and ProtT5) and an antibody-specific protein language model (PLM) (Antiberty). These models were trained in a transfer learning network to predict the outcomes in the BVP assay and the bovine serum albumin binding assay, which was developed as a complement to the BVP assay. The training was conducted on a large dataset of antibody sequences augmented with experimental conditions, which were collected through a highly efficient application system.</p><p><strong>Results: </strong>The resulting models demonstrated robust performance on canonical mAbs (monospecific with heavy and light chain), bispecific Abs, and single-domain Fc (VHH-Fc). PLMs outperformed a model built using molecular descriptors calculated from AlphaFold 2 predicted structures. Embeddings from the antibody-specific and foundational PLMs resulted in similar performance.</p><p><strong>Conclusion: </strong>To our knowledge, this represents the first application of PLMs to predict assay data on bispecifics and VHH-Fcs.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"7 3","pages":"199-208"},"PeriodicalIF":0.0,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11259759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141735159","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 case study of a bispecific antibody manufacturability assessment and optimization during discovery stage and its implications.","authors":"Shuang Wang, Weijie Zhang, Baotian Yang, Xudong Zhang, Jing Fang, Haopeng Rui, Zhijian Chen, Jijie Gu, Zhiqiang Chen, Jianqing Xu","doi":"10.1093/abt/tbae013","DOIUrl":"10.1093/abt/tbae013","url":null,"abstract":"<p><p>The manufacturability assessment and optimization of bispecific antibodies (bsAbs) during the discovery stage are crucial for the success of the drug development process, impacting the speed and cost of advancing such therapeutics to the Investigational New Drug (IND) stage and ultimately to the market. The complexity of bsAbs creates challenges in employing effective evaluation methods to detect developability risks in early discovery stage, and poses difficulties in identifying the root causes and implementing subsequent engineering solutions. This study presents a case of engineering a bsAb that displayed a normal solution appearance during the discovery phase but underwent significant precipitation when subjected to agitation stress during 15 L Chemistry, Manufacturing, and Control (CMC) production Leveraging analytical tools, structural analysis, <i>in silico</i> prediction, and wet-lab validations, the key molecular origins responsible for the observed precipitation were identified and addressed. Sequence engineering to reduce protein surface hydrophobicity and enhance conformational stability proved effective in resolving agitation-induced aggregation. The refined bsAb sequences enabled successful mass production in CMC department. The findings of this case study contribute to the understanding of the fundamental mechanism of agitation-induced aggregation and offer a potential protein engineering procedure for addressing similar issues in bsAb. Furthermore, this case study emphasizes the significance of a close partnership between Discovery and CMC teams. Integrating CMC's rigorous evaluation methods with Discovery's engineering capability can facilitate a streamlined development process for bsAb molecules.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"7 3","pages":"189-198"},"PeriodicalIF":0.0,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11259756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141735244","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 new mechanism of antibody diversity: formation of the natural antibodies containing LAIR1 and LILRB1 extracellular domains","authors":"Yuanzhi Chen, Zhiren Zeng, Ziyou Chen, Na Yuan, Xinya Ye, Chengcheng Zhang, N. Xia, Wenxin Luo","doi":"10.1093/abt/tbae008","DOIUrl":"https://doi.org/10.1093/abt/tbae008","url":null,"abstract":"\u0000 The recent discovery of public antibodies targeting Plasmodium falciparum-encoded repetitive interspersed families of polypeptides (RIFINs), which contain extracellular immunoglobulin-like domains from LAIR1 or LILRB1, constitutes a significant step forward in comprehending the reactivity of the Plasmodium parasite. These antibodies arise from unique B cell clones and demonstrate extensive cross-reactivity through their interaction with Plasmodium falciparum RIFINs. LAIR1 and LILRBs are specialized type I transmembrane glycoproteins, classified as immune inhibitory receptors, restricted to primates and mainly found on hematopoietic cells. They are instrumental in modulating interactions within the tumor microenvironment and across the immune system, and are increasingly recognized as important in anti-cancer immunotherapy and pathogen defense. The presence of LAIR1/LILRB1-containing antibodies offers new insights into malaria parasite evasion strategies and the immune system’s response. Additionally, the innovative method of integrating extra exons into the antibody switch region is a noteworthy advancement, enriching the strategies for the generation of a varied array of bispecific and multispecific antibodies.","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"25 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141113760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Role of antibody engineering in generation of derivatives starting from MOv19 MAb: 40 years of biological/therapeutic tools against folate receptor alfa","authors":"","doi":"10.1093/abt/tbae010","DOIUrl":"https://doi.org/10.1093/abt/tbae010","url":null,"abstract":"","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"51 16","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140975351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}