Antibody Therapeutics最新文献

{"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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}

{"title":"A VHH single-domain platform enabling discovery and development of monospecific antibodies and modular neutralizing bispecifics against SARS-CoV-2 variants","authors":"Marisa L Yang, Tom Z. Yuan, Kara Y Chan, Lin Ding, Zhen Han, Hector Franco, Carson Holliday, Shruthi Kannan, E. Davidson, B. Doranz, K. Chandran, E. H. Miller, Jessica A. Plante, Scott C Weaver, Eunice Cho, Shweta Kailasan, Lukas Marsalek, Hoa Giang, Y. Abdiche, Aaron Sato","doi":"10.1093/abt/tbae009","DOIUrl":"https://doi.org/10.1093/abt/tbae009","url":null,"abstract":"\u0000 \u0000 \u0000 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve, escape coronavirus disease 2019 therapeutics and vaccines, and jeopardize public health.\u0000 \u0000 \u0000 \u0000 To combat SARS-CoV-2 antigenic escape, we developed a rapid, high-throughput pipeline to discover monospecific VHH antibodies and iteratively develop VHH-Fc-VHH bispecifics capable of neutralizing emerging SARS-CoV-2 variants.\u0000 \u0000 \u0000 \u0000 By panning VHH single-domain phage libraries against ancestral or Beta spike proteins, we discovered high-affinity VHH antibodies with unique target epitopes. Combining two VHHs into a tetravalent bispecific construct conferred broad neutralization activity against multiple variants and was more resistant to antigenic escape than the monospecific antibody alone. Following the rise of the Omicron variant, a VHH in the original bispecific construct was replaced with another VHH discovered against Omicron BA.1 receptor binding domain—the resulting bispecific exhibited neutralization against both BA.1 and BA.5 sublineage variants.\u0000 \u0000 \u0000 \u0000 A heavy chain-only tetravalent VHH-Fc-VHH bispecific platform derived from humanized synthetic libraries held a myriad of unique advantages: 1) synthetic preconstructed libraries minimized risk of liabilities and maximized discovery speed, 2) VHH scaffolds allowed for a modular “plug-and-play” format that could be rapidly iterated upon as variants of concern arose, 3) natural dimerization of single VHH-Fc-VHH polypeptides allowed for straightforward bispecific production and purification methods, and 4) multivalent approaches enhanced avidity boosting effects and neutralization potency, and conferred more robust resistance to antigenic escape than monovalent approaches against specific variants. This iterative platform of rapid VHH discovery combined with modular bispecific design holds promise for long-term viral control efforts.\u0000","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141017619","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":"Structure and function of therapeutic antibodies approved by the US FDA in 2023","authors":"William R Strohl","doi":"10.1093/abt/tbae007","DOIUrl":"https://doi.org/10.1093/abt/tbae007","url":null,"abstract":"\u0000 In calendar year 2023, the United States Food and Drug Administration (US FDA) approved a total of 55 new molecular entities (NMEs), of which 12 were in the class of therapeutic antibodies. Besides antibody protein drugs, the US FDA also approved another five non-antibody protein drugs, making the broader class of protein drugs about 31% of the total approved drugs. Amongst the 12 therapeutic antibodies approved by the US FDA, eight were relatively standard IgG formats, three were bivalent, bispecific antibodies, and one was a trivalent, bispecific antibody. In 2023, no new antibody-drug conjugates, immunocytokines, or chimeric antigen receptor T (CAR-T) cells were approved. Of the approved antibodies, two targeted programmed cell death receptor (PD)-1 for orphan indications, two targeted CD20 for diffuse large B cell lymphoma (DLBCL), two different targets (B-cell maturation antigen [BCMA] and G-coupled protein receptor class C, group 5, member D [GPRC5D]) for treatment of multiple myeloma (MM), and one each that targeted amyloid-β protofibrils for Alzheimer’s disease, neonatal Fc receptor (FcRn) alpha-chain for myasthenia gravis, complement factor C5 for CD55 deficiency with Hyper-activation of complement, Angiopathic thrombosis, and severe Protein-Losing Enteropathy (CHAPLE) disease, interleukin (IL)-23p19 for severely active ulcerative colitis, IL-17A-F for plaque psoriasis, and respiratory syncytial virus (RSV)-F protein for season-long RSV prophylaxis in infants.","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140229908","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":"Development of a novel humanized anti-TSLP monoclonal antibody HZ-1127 with anti-allergic diseases and cancer potential","authors":"Xiaolei Liu, Jianzhong Han, Qian Wang, Peng Wang, Li Li, Kehe Du, Fengchao Jiang, Pei Zhang, Hongjun Liu, Jian Huang","doi":"10.1093/abt/tbae006","DOIUrl":"https://doi.org/10.1093/abt/tbae006","url":null,"abstract":"Abstract Thymic stromal lymphopoietin (TSLP) is a member of the IL-2 cytokine family and has been widely recognized as a master regulator of type 2 inflammatory responses at barrier surfaces. Recent studies found dysregulation of the TSLP–TSLP receptor (TSLPR) pathway is associated with the pathogenesis of not only allergic diseases but also a wide variety of cancers including both solid tumors and hematological tumors. Thus, the blockade of TSLP represents an attractive therapeutic strategy for allergic diseases and cancer. In this study, we report the development of a novel humanized anti-TSLP monoclonal antibody (mAb) HZ-1127. Binding affinity, specificity, and ability of HZ-1127 in inhibiting TSLP were tested. HZ-1127 selectively binds to the TSLP cytokine with high affinity and specificity. Furthermore, HZ-1127 dramatically inhibits TSLP-dependent STAT5 activation and is more potent than Tezepelumab, which is an FDA-approved humanized mAb against TSLP for severe asthma treatment in inhibiting TSLP-induced CCL17 and CCL22 chemokines secretion in human peripheral blood mononuclear cells. Our pre-clinical study demonstrates that HZ-1127 may serve as a potential therapeutic agent for allergic diseases and cancer.","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140425694","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":"Reforming solid tumor treatment: the emerging potential of smaller format antibody-drug conjugate","authors":"Xiaojie Ma, Mingkai Wang, Tianlei Ying, Yan-ling Wu","doi":"10.1093/abt/tbae005","DOIUrl":"https://doi.org/10.1093/abt/tbae005","url":null,"abstract":"Abstract In recent years, substantial therapeutic efficacy of antibody-drug conjugates (ADCs) has been validated through approvals of 16 ADCs for the treatment of malignant tumors. However, realization of the maximum clinical use of ADCs requires surmounting extant challenges, mainly the limitations in tumor penetration capabilities when targeting solid tumors. To resolve the hurdle of suboptimal tumor penetration, miniaturized antibody fragments with engineered formats have been harnessed for ADC assembly. By virtue of their reduced molecular sizes, antibody fragment-drug conjugates hold considerable promise for efficacious delivery of cytotoxic agents, thus conferring superior therapeutic outcomes. This review will focus on current advancements in novel ADC development utilizing smaller antibody formats from ~6 to 80 kDa, with particular emphasis on single-domain antibodies, which have been widely applied in novel ADC design. Additionally, strategies to optimize clinical translation are discussed, including half-life extension, acceleration of internalization, and reduction of immunogenic potential.","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140453684","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}